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Solid-phase Synthesis of [4.4] Spirocyclic Oximes
Published on: February 6, 2019
Engineering Imine Reductase for the Synthesis of Pharmaceutically Relevant 1-Aminomethylbenzocycloalkanes via Dynamic
Xiaoshi Lv1,2,3, Zefei Xu2, Xiangtao Liu2
1College of Life Sciences and State Key Laboratory of Medicinal Chemical Biology, Nankai University, 94 Weijin Road, Tianjin 300071, China.
Abstract:
Asymmetric synthesis of chiral 1-aminomethylbenzocycloalkanes remains challenging. Here, an imine reductase variant (IR215-L97F/L187Q/A239M) was identified, showing a 277-fold increase in the catalytic efficiency and enhanced stereoselectivity (>99% ee) for the synthesis of (1S)-4,5-dimethoxy-1-[(methylamino)methyl]benzocyclobutane (a key intermediate of ivabradine). This variant enabled the synthesis of a range of different substituted chiral 1-aminomethylbenzocyclobutanes and one example of a 1-aminomethylbenzocyclohexane with up to >99% ee values and 89% isolated yield, providing an efficient protocol for accessing pharmaceutically valuable compounds.
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